| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Prevention of infections caused by Corynebacterium diphtheriae, Clostridium tetani, Bordetella pertussis, poliovirus type 1, 2 and 3, prevention against invasive infections caused by Haemophilus influenzae type b and infection caused by hepatitis B virus |
|
| E.1.1.1 | Medical condition in easily understood language |
| Active immunisation against diphtheriae, tetanus, pertussis, hepatitis B, poliomyelitis and invasive infections caused by Haemophilus influenzae type b |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10036897 |
| E.1.2 | Term | Prophylactic vaccination |
| E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| E.1.2 | Level | HLGT |
| E.1.2 | Classification code | 10043413 |
| E.1.2 | Term | Therapeutic procedures and supportive care NEC |
| E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10021430 |
| E.1.2 | Term | Immunisation |
| E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10021431 |
| E.1.2 | Term | Immunisations |
| E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Groups 1 and 2 only
To demonstrate the non-inferiority of the DTaP-IPV-HB-Hib vaccine to the control Infanrix hexa vaccine, both co-administered with Prevenar 13, in terms of seroprotection or vaccine response rates to PT, FHA, Hep B, and PRP antigens, 1 month after a 3-dose primary series. |
|
| E.2.2 | Secondary objectives of the trial |
Immunogenicity
Groups 1 and 2
• To describe in each group the immunogenicity parameters before the
first vaccination for PT and FHA antigens and 1 month after the third
dose of the primary series for all antigens contained in the
investigational and control vaccines
• To describe in each group the immune response to Prevenar 13
serotypes 1 month after the 3rd dose of the primary series
• To describe the immune response to RotaTeq vaccine before the first
vaccination and 1 month after the 3rd dose
Group 3
• To describe the immunogenicity parameters before the first
vaccination and 1 month after the 3rd dose of the primary series for all
antigens contained in the investigational and Pentavac vaccines
• To describe the immune response to RotaTeq vaccine before the first
vaccination and 1 month after the 3rd dose
Safety (all Groups)
To describe the safety profile after each and any injection for each of the
study groups. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
An individual must fulfill all of the following criteria in order to be eligible for trial enrollment:
All Groups
1) Aged 55 to 75 days on the day of the first study visit
2) Born at full term of pregnancy (≥ 37 weeks) and/or with a birth weight ≥ 2.5 kg
3) Informed consent form has been signed and dated by the parent(s) or other legally acceptable representative (and by an independent witness if required by local regulations)
4) Subject and parent/legally acceptable representative are able to attend all scheduled visits and to comply with all trial procedures
5) Covered by health insurance, if applicable
Group 3 only
6) Previously vaccinated with one dose of hepatitis B vaccine |
|
| E.4 | Principal exclusion criteria |
An individual fulfilling any of the following criteria is to be excluded from trial enrollment:
1) Participation at the time of study enrollment (or in the 4 weeks preceding the first trial vaccination) or planned participation during the present trial period in another clinical trial investigating a vaccine, drug, medical device, or medical procedure
2) Receipt of any vaccine in the 4 weeks preceding the first trial vaccination or planned receipt of any vaccine in the 4 weeks following any trial vaccination, except in case of routine vaccines to be administered as per the National Immunization schedule and for influenza vaccination. This exception includes monovalent pandemic influenza vaccines and multivalent influenza vaccines
3) Groups 1 and 2 only: Previous vaccination against diphtheria, tetanus, pertussis, poliomyelitis, hepatitis B, or Haemophilus influenzae type b, pneumococcal infections, and rotavirus with another vaccine(s)
4) Group 3 only: Previous vaccination against diphtheria, tetanus, pertussis, poliomyelitis, Haemophilus influenzae type b, pneumococcal and meningococcal infections, and rotavirus with another vaccine(s)
5) Receipt of immune globulins, blood or blood-derived products since birth
6) Known or suspected congenital or acquired immunodeficiency; or receipt of immunosuppressive therapy, such as anti-cancer chemotherapy or radiation therapy, since birth; or long-term systemic corticosteroid therapy (prednisone or equivalent for more than 2 consecutive weeks since birth)
7) Known personal or maternal history of hepatitis B (HBsAg) or hepatitis C seropositivity
8) History of diphtheria, tetanus, pertussis, poliomyelitis, hepatitis B, or Haemophilus influenzae type b and pneumococcal infections, confirmed either clinically, serologically, or microbiologically
9) Known systemic hypersensitivity to any of the vaccine components, or history of a life-threatening reaction to the vaccine(s) used in the trial or to a vaccine containing any of the same substances
10) Known thrombocytopenia, as reported by the parent/legally acceptable representative
11) Bleeding disorder, or receipt of anticoagulants in the 3 weeks preceding inclusion, contraindicating intramuscular vaccination
12) History of seizures
13) Subjects in an emergency setting, or hospitalized involuntarily
14) Chronic illness that, in the opinion of the Investigator, is at a stage where it might interfere with trial conduct or completion
15) Moderate or severe acute illness/infection (according to Investigator judgment) on the day of vaccination or febrile illness (temperature ≥ 38.0°C). A prospective subject should not be included in the study until the condition has resolved or the febrile event has subsided.
16) Identified as a natural or adopted child of the Investigator or employee with direct involvement in the proposed study |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Groups 1 and 2 only
The following serological endpoints will be assessed 1 month after the third dose of the primary series (i.e., at V04 = 5 MoA) with seroprotection and vaccine response being respectively defined as:
Seroprotection for Hep B and PRP:
• Anti-Hep B antibody (Ab) concentrations ≥ 10 mIU/mL
• Anti-PRP Ab concentrations ≥ 0.15 µg/mL
Vaccine response for PT and FHA:
• Post-Dose 3 Ab concentrations ≥ 4 x lower level of quantitation (LLOQ), if pre-Dose 1 Ab concentrations < 4 x LLOQ
• Post-Dose 3 Ab concentrations ≥ pre-Dose 1 Ab concentrations, if pre-Dose 1 Ab concentrations ≥ 4 x LLOQ |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Vaccination
Groups 1 and 2: subjects will receive 3 doses of either DTaP-IPV-HB-Hib or Infanrix hexa, both co-administered with Prevenar 13 and RotaTeq on Day 0 (2 MoA), Day 30 (3 MoA), and Day 60 (4 MoA).
Group 3: subjects will receive 2 doses of DTaP-IPV-HB-Hib vaccine on Day 0 (2 MoA) and Day 120 (6 MoA) and 1 dose of Pentavac on Day 60 (4 MoA). Investigational vaccine and Pentavac will be co-administered with Prevenar 13 on Day 0 (2 MoA) and Day 60 (4 MoA), with NeisVac-C on Day 0 (2 MoA), and with RotaTeq on Day 0 (2 MoA), Day 60 (4 MoA) and Day 120 (6 MoA).
Blood sampling
All subjects will provide a pre-vaccination blood sample at Day 0 (V01 at 2 MoA) and one post-vaccination sample at Day 90 (V04 at 5 MoA) for Groups 1 and 2 and at Day 150 (V04 at 7 MoA) for Group 3. |
|
| E.5.2 | Secondary end point(s) |
Immunogenicity
Groups 1 and 2
Endpoints for the immune response (descriptive) will include:
V01 at 2 MoA:
• Ab concentrations for PT and FHA antigens
• Ab concentrations above a cut-off:
• Anti-PT Ab concentrations ≥ LLOQ
• Anti-FHA Ab concentrations ≥ LLOQ
• Anti-RV IgA ≥ 20 U/mL
V04 at 5 MoA:
• Ab concentrations/titers for each valence
• Ab concentrations /titers above a cut-off:
• Anti-D Ab concentrations ≥ 0.01 IU/mL, ≥ 0.1 IU/mL and ≥ 1.0 IU/mL
• Anti-T Ab concentrations ≥ 0.01 IU/mL, ≥ 0.1 IU/mL and ≥ 1.0 IU/mL
• Anti-PT Ab concentrations ≥ 4 EU/mL
• Anti-FHA Ab concentrations ≥ 4 EU/mL
• Anti-poliovirus 1, 2, and 3 Ab titers ≥ 8 (1/dil)
• Anti-Hep B Ab concentrations ≥ 100 mIU/mL
• Anti-PRP Ab concentrations ≥ 1.0 µg/mL
• Anti-pneumococcal serotype 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F concentrations ≥ 0.35 µg/mL
• Anti-RV IgA ≥ 20 U/mL
• Ab individual concentrations ratios for anti-PT and FHA (V04 at 5MoA/V01 at 2MoA)
• Seroconversion for anti PT and anti FHA, defined as anti PT and anti FHA ≥ 4 fold Ab concentrations increase from V01 (at 2 MoA) to V04 (at 5 MoA)
• Seroconversion for anti-RV IgA defined as anti-RV IgA ≥ 20 U/mL, in
subject seronegative at pre-Dose 1)
Group 3
V01 at 2 MoA:
• Ab concentrations /titers for each valence (except Prevenar 13)
• Ab concentrations /titers above a cut-off:
• Anti-D Ab concentrations ≥ 0.01 IU/mL and ≥ 0.1 IU/mL
• Anti-T Ab concentrations ≥ 0.01 IU/mL and ≥ 0.1 IU/mL
• Anti-PT Ab concentrations ≥ LLOQ
• Anti-FHA Ab concentrations ≥ LLOQ
• Anti-poliovirus 1, 2, and 3 Ab titers ≥ 8 (1/dil)
• Anti-Hep B Ab concentrations ≥ 10 mIU/mL
• Anti- PRP Ab concentrations ≥ 0.15 µg/mL
• Anti-RV IgA ≥ 20 U/mL
V04 at 7 MoA:
• Ab concentrations /titers for each valence (except Prevenar 13)
• Ab concentrations /titers above a cut-off:
• Anti-D Ab concentrations ≥ 0.01 IU/mL, ≥ 0.1 IU/mL and ≥ 1.0 IU/mL
• Anti-T Ab concentrations ≥ 0.01 IU/mL, ≥ 0.1 IU/mL and ≥ 1.0 IU/mL
• Anti-PT Ab concentrations ≥ 4 EU/mL
• Anti-FHA Ab concentrations ≥ 4 EU/mL
• Anti-poliovirus 1, 2, and 3 Ab titers ≥ 8 (1/dil)
• Anti-Hep B Ab concentrations ≥ 10 mIU/mL and ≥ 100 mIU/mL
• Anti-PRP Ab concentrations ≥ 0.15 µg/mL and ≥ 1.0 µg/mL
• Anti-RV IgA ≥ 20 U/mL
• Ab individual concentrations /titer ratios for all antigens (V04/V01) (except Prevenar 13)
• Seroconversion for anti PT and anti FHA, defined as anti PT and anti FHA ≥ 4 fold Ab concentration increase from V01 (at 2 MoA) to V04 (at 7 MoA)
• Seroconversion for anti-RV IgA defined as anti-RV IgA ≥ 20 U/mL, in subject seronegative at pre-Dose 1)
Vaccine response for PT and FHA:
• Post-Dose 3 Ab concentrations ≥ 4 x lower level of quantitation (LLOQ), if pre-Dose 1 Ab concentrations < 4 x LLOQ
• Post-Dose 3 Ab concentrations ≥ pre-Dose 1 Ab concentrations, if pre-Dose 1 Ab concentrations ≥ 4 x LLOQ
Safety (all Groups)
• Occurrence of any unsolicited systemic adverse events (AEs) reported in the 30 minutes after each and any dose
• Occurrence of solicited, i.e., pre-listed in the subject’s diary and electronic case report form (eCRF), injection site and systemic reactions occurring up to 7 days after each and any dose
• Occurrence of unsolicited (spontaneously reported) AEs up to 30 days after each and any dose
• Occurrence of SAEs, including AESIs, throughout the trial period
• Other endpoints recorded or derived as described in the statistical analysis plan. Depending on the item, these could include: nature (MedDRA preferred term), time of onset, duration, number of days of occurrence, Grade of severity, relationship to vaccine, action taken, whether the AE led to early termination from the study, seriousness, or outcome. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Vaccination
Groups 1 and 2: subjects will receive 3 doses of either DTaP-IPV-HB-Hib or Infanrix hexa, both co-administered with Prevenar 13 and RotaTeq on Day 0 (2 MoA), Day 30 (3 MoA), and Day 60 (4 MoA).
Group 3: subjects will receive 2 doses of DTaP-IPV-HB-Hib vaccine on Day 0 (2 MoA) and Day 120 (6 MoA) and 1 dose of Pentavac on Day 60 (4 MoA). Investigational vaccine and Pentavac will be co-administered with Prevenar 13 on Day 0 (2 MoA) and Day 60 (4 MoA), with NeisVac-C on Day 0 (2 MoA), and with RotaTeq on Day 0 (2 MoA), Day 60 (4 MoA) and Day 120 (6 MoA).
Blood sampling
All subjects will provide a pre-vaccination blood sample at Day 0 (V01 at 2 MoA) and one post-vaccination sample at Day 90 (V04 at 5 MoA) for Groups 1 and 2 and at Day 150 (V04 at 7 MoA) for Group 3. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | Yes |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| blind-observer (group 1 and group 2) and open-label (group 3) |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 16 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 46 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 12 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 12 |
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